Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000804266 | SCV000944168 | likely pathogenic | Hereditary breast ovarian cancer syndrome | 2020-11-25 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine with glycine at codon 24 of the BRCA1 protein (p.Cys24Gly). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with breast cancer (PMID: 28664449). ClinVar contains an entry for this variant (Variation ID: 649351). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt BRCA1 protein function. This variant disrupts the p.Cys24 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 25823446, 20103620, 18489799, 11320250), and experimental studies suggest this cysteine residue is critical for protein function (PMID: 11526114, 22843421, 21725363, 23161852, 25823446, 30209399). As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Ambry Genetics | RCV002360967 | SCV002662619 | pathogenic | Hereditary cancer-predisposing syndrome | 2020-06-03 | criteria provided, single submitter | clinical testing | The p.C24G pathogenic mutation (also known as c.70T>G), located in coding exon 1 of the BRCA1 gene, results from a T to G substitution at nucleotide position 70. The cysteine at codon 24 is replaced by glycine, an amino acid with highly dissimilar properties. This alteration was identified in a cohort of 313 unselected individuals with breast cancer from China (Li G et al. J. Cancer Res. Clin. Oncol., 2017 Oct;143:2011-2024). This variant is non-functional in multiple assays including BARD1 binding, E3 Ubiquitin Ligase activity and a haploid cell survival assay (Findlay GM. Nature. 2018 10;562(7726):217-222; Starita LM et al. Genetics, 2015 Jun;200:413-22). Based on internal structural assessment, this alteration disrupts one of the Zn-binding sites of the BRCA1 RING domain (Ambry internal data; Brzovic PS et al. Nat. Struct. Biol., 2001 Oct;8:833-7). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Multiple pathogenic alterations are located at this position highlighting its sensitivity to amino acid substitution (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV004997350 | SCV005626150 | pathogenic | not provided | 2024-05-17 | criteria provided, single submitter | clinical testing | The BRCA1 c.70T>G (p.Cys24Gly) variant has been reported in the published literature in one individual with breast cancer (PMID: 28664449 (2017)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). The variant is located in a region that is considered important for protein function and/or structure (PMID: 16403807 (2006), PMID: 20103620 (2010)). Experimental studies demonstrated that this variant was damaging to protein function (PMID: 25823446 (2015), PMID: 30209399 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. |
| Brotman Baty Institute, |
RCV001077752 | SCV001243734 | not provided | Breast-ovarian cancer, familial, susceptibility to, 1 | no assertion provided | in vitro |